ABSTRACT The Big South/West Node of the NIDA Clinical Trials Network (CTN) represents an expansion of the Texas Node that has been a part of the CTN since 2005. With this expansion, the node will now be guided by the shared leadership of Madhukar H. Trivedi, MD of University of Texas Southwestern Medical Center (UTSW) Steven Shoptaw, PhD of UCLA, and Jennifer S. Potter, PhD, MPH, of UT Health Science Center at San Antonio (UTHSCSA). This fourth competing renewal application builds on our successful track record of leading CTN trials, being good network partners by providing excellent sites for multi-site studies, high productivity in publishing, and training the next generation of scientists. During the 2015-2020 funding cycle, our team developed and led: the largest pharmacotherapy trial for the treatment of methamphetamine use disorder to date (extended-release naltrexone plus high-dose bupropion; CTN0068 ADAPT-2), an in-depth study of the causes of death in a cohort of people living with HIV/HCV and substance use disorder (CTN0064A1), and an implementation study to develop and deploy universal screening for opioid use disorder and measurement based care using buprenorphine (CTN0090 MBC4OUD). Finally, a study testing transcranial magnetic stimulation (TMS) as a treatment for stimulant use disorder has been approved for development, in collaboration with the Southern Consortium Node (CTN0108). For this renewal application, we capitalize on the experience of the Multiple PIs, who collectively have expertise in the treatment of stimulants, the treatment of and public health response to the opioid crisis, and the treatment and care of HIV. Additional investigators bring content expertise spanning addiction science and clinical care, translational science, dissemination and implementation science, informatics, and trial implementation. The expanded Big South/West Node is named to denote the importance of including geographic regions in the South that have historically not been represented within the CTN (i.e., Arkansas, Oklahoma, Louisiana). This geographical expansion provides greater access to diverse patient populations (e.g., diverse racial and ethnic groups; underinsured; underserved; native [American Indian] and immigrant groups) within diverse settings (e.g., rural, urban). Our existing partnerships with primary care networks, large health care systems, and use of electronic health records (EHR) to positively impact substance use, has been further broadened to include multiple statewide networks and resources in new partner states. Our research agenda includes a focus on the fourth wave of the opioid epidemic, building upon the expertise of our investigators in treating stimulant and opioid use disorders, and the changing needs of the regions we serve. Our team has experience with innovative study designs that target all areas of the translational science continuum, and equip our Node to successfully and significantly improve the care of persons who misuse substances.